The chemical name of duloxetine hydrochloride is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine hydrochloride (1).
Duloxetine was disclosed in U.S. Pat. No. 4,956,388 and its acid addition salts in U.S. Pat. No. 5,362,886. Duloxetine hydrochloride is useful for the treatment as an anti-depressant and also for treatment of urinary incontinence. It is the active ingredient of drug “CYMBALTA”.
Very few references are directed towards chiral synthesis of chiral starting compound (S)—N.N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine of formula
and it's use in the asymmetric synthesis of duloxetine.
Numbers of documents are cited in the patent as well as academic literature for the synthesis of duloxetine and its enantiomerically pure intermediate compounds via an optical resolution of racemic duloxetine or racemic intermediates that are formed in the synthesis of duloxetine at different steps. These pathways are illustrated in the following synthetic scheme I.

Most of the literature data indicate that the initial step of duloxetine synthesis is condensation of either racemic hydroxy compound i.e. (RS)—N.N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine or enantiomerically pure (S)—N.N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine with 1-fluoronaphthalene by using sodium hydride as base in polar aprotic solvent. Sodium hydride is very hazardous reagent because it is pyrophoric and reacts violently with water with evolution of hydrogen gas.
The inventors of WO 2004/056,795 have successfully replaced sodium hydride with alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates preferably with potassium hydroxide but the condensation reaction requires to be carried out in presence of phase transfer catalyst such as crown ethers, quaternary ammonium salts, quaternary phosphonium salts to facilitate the reaction. The use of phase transfer catalysts render the process economically non viable since they are much costlier.
U.S. Pat. No. 6,541,668 describes synthesis of 3-aryloxy-3-arylpropanamines by reaction of alkoxide of 3-hydroxy-3-arylpropanamine with a halo-aromatic in 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone as solvent. The alkoxides are very strong bases and therefore are hazardous that brings limitation on their use on large scale.
WO 2006/126,213 describe condensation of racemic hydroxy compound with 1-fluoronaphthalene in organic polar solvent such as dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide in presence of alkoxide base such as sodium methoxide, sodium ethoxide and potassium tert. butoxide. As mentioned above, the alkoxides are very strong bases and hazardous which restrict their use on plant scale reactions.
Thus, the methods described in prior art for condensation of racemic hydroxy compound with 1-fluoronaphthalene that utilizes sodium hydride, alkoxide or phase transfer catalyst for large-scale reactions suffers from several drawbacks, such as:                1) potentially hazardous reagents are used,        2) sodium hydride pyrophoric, it catches fire on contact with moisture,        3) very toxic reagents are used,        4) requires special skills to handle,        5) requires anhydrous medium for performing the reaction,        6) costlier reagent and        7) difficult to carry out plant scale reactions.        
These drawbacks of the condensation reactions associated with the prior art processes are overcome by the present invention in which the condensation is achieved by using milder bases such as sodamide potassium amide and potassium bis(trimethylsilyl)amide (see scheme II).
There are several reports on optical resolution of racemic duloxetine and it's racemic intermediates by using resolving chiral acids such as tartaric acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-L-tartaric acid, mandelic acid, camphor sulphonic acid, (S)-2-pyrrolidine-2-one-5-carboxylic-acid and (−)-2,3,4,6-di-O-isopropylidine-2-keto-L-gulonic acid. However, very few of them are directed towards resolution of racemic condensed compound (RS)—N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5a+5b) to obtain (S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl) propanamine (5a), which is key intermediate in synthesis of duloxetine hydrochloride. Theses references are discussed below.
The example 1 of U.S. Pat. No. 5,023,269 discloses general method for preparation of (R,S)N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b) that is isolated as its oxalate salt. This patent although mentions that the resolution of racemic mixture 5a+5b can be carried out using resolving agent such as dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid (referred to as DBTA hereafter) and the like, however, it does not provide an enabling disclosure for the same.
WO 2006/045255 teaches the use of D-tartaric acid to resolve racemic N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b) followed by two recrystallizations of the resulting tartarate salt from tetrahydrofuran as solvent to preferentially isolate (S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine-(D)-tartarate salt in 25% yield and 99% chiral purity.
WO 2006/027798 teaches use of di-p-toluloyl-L-tartaric acid as a resolving agent for resolution of racemic N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b) to obtain (S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine-di-p-toluoyl-(L)-tartarate salt in 34.8% yield and having chiral purity of about 98%. This PCT application further mentions about poor efficiency of dibenzoyl-L-tartaric acid and higher cost of chiral resolving agents such as (S)-2-pyrrolidine-2-one-5-carboxylic-acid and (−)-2,3,4,6-di-O-isopropylidine-2-keto-L-gulonic acid.
WO 2006/126213 teaches resolution of racemic N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b) using D(−)-tartaric acid from ethyl acetate-isopropyl alcohol solvent mixture to get (S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine-(D)-tartarate salt as hemi hydrate in 22% yield.
US 2006/0270861 A1 covers a process for preparing enantiomerically enriched (S)-(+)-N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5b) by resolution of (R,S)—N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5a+5b) with an enantiomerically pure acid that include dibenzoyl-L-tartaric acid also, however, it does not provide any enabling disclosure for use of dibenzoyl-L-tartaric acid.
The inventors of the present invention have developed a novel process for optical resolution of racemic condensed compound (RS)—N.N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5a+5b) with di-benzoyl-L-tartaric acid (DBTA) and di-p-anisoyl-L-tartaric acid (DATA) as resolving agents.
None of the prior art references discussed above provide an enabling disclosure for use of DBTA or DATA as a resolving agent for resolution of (R,S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b). Further the methods reported in prior art for resolution of (R,S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5a+5b) either provide misleading information or have several disadvantages, as discussed below:    1. The patent application WO 2006/027798 states that chiral acids such as dibenzoyl tartaric acids, mandelic acid and camphorsulphonic acid have been found to be ineffective resolving agent,    2. The process as disclosed in the patent applications WO2006/126213 and WO2006/027798 uses ethyl acetate-isopropyl alcohol mixture and ethyl acetate respectively as solvents. The present inventors have studied efficiency of DBTA in these solvents along with other solvents. The results of this comparative study is provided in table 1 below which reveals that resolution was poor in ethyl acetate and in the mixture of ethyl acetate-IPA as solvent. In ethyl acetate as solvent, the content of R isomer in the product obtained after resolution was as high as 8.2% while with ethyl acetate-IPA mixture it was 7.0%.    3. The resolving agents like (S)-2-pyrrolidine-2-one-5-carboxylic-acid, (−)-2,3,4,6-di-O-isopropylidine-2-keto-L-gulonic acid, mandelic acid and camphorsulphonic acid that are used in prior art are very expensive, rendering the method uneconomical.    4. The resolution methods discussed in prior art gives (S)—N,N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine (5b) in comparatively low chiral purity e.g. the resolution method discussed in WO2006/45255 gives 99% chiral purity while the process in WO2006/027798 gives 98% ee.
The preparation 2 of example 2 of U.S. Pat. No. 5,362,886 describes crystallization of duloxetine hydrochloride from ethyl acetate but without providing any data on the crystalline form. The later U.S. patent application 2006/0270859 state that the crystalline duloxetine hydrochloride obtained by the process described in U.S. Pat. No. 5,362,886 is anhydrous form which is referred as Form A. The patent application 2006/0270859 covers another crystalline Form B of duloxetine hydrochloride and process for its preparation that comprises of providing solution of duloxetine hydrochloride in water and a solvent selected from the group consisting of C1-4 alcohols and removing the solvent.
Another U.S. patent application 2006/0276660 A1 describe process for purification of duloxetine hydrochloride comprising crystallization of duloxetine hydrochloride from water or a solvent selected from group consisting of C3-8 ketones, C3-8 esters, C2-8 ethers, C2-8 alcohols and mixtures thereof with water.
WO 2007/077580 A2 describe process for purification of duloxetine hydrochloride comprising crystallization of duloxetine hydrochloride from solvent or mixture of solvents selected from ester solvents like methyl acetate, ethyl acetate, ethyl formate, propyl acetate, isopropyl acetate, methyl isopropyl acetate and or alcohol solvents like methanol, ethanol, isopropyl alcohol or mixture of ester and alcohol solvents.
EP 1,820,800 A1 mentions that Form A of duloxetine hydrochloride may be crystallized out of a solution of duloxetine hydrochloride in water; alcohols, such as, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol, 2-methoxyethanol, 2,2,2-trifluoroethanol; or acetonitrile, nitromethane, 1,2-dimethoxyethane; or esters, such as methyl acetate, ethyl acetate, ethyl formate; or ketones, such as e.g. acetone, 2-butanone; or mixtures thereof, or mixtures with water.
The present invention provides a process for crystallization of duloxetine hydrochloride (1) from a solvent selected from alcohols such as methanol, ethanol, n-propanol, isopropanol; ketones such as acetone, methyl ethyl ketone; esters such as methyl acetate, ethyl acetate, ethyl formate, propyl acetate or a mixtures thereof.
In summary, the inventors of the present invention have developed a process for preparation of duloxetine hydrochloride (1) having chiral purity greater than 99.9% that not only overcome the disadvantages of processes in the prior art but also is safer, efficient, economically viable and easy to operate on plant scale. The process is discussed below in detail.